My career goal is to become an established researcher in the molecular epidemiology of cancer. This goal builds upon my previous education and training in medicine and epidemiology but requires further training in molecular techniques and genetic epidemiology. At the end of this training period, I will be an established researcher in this field. I have developed a comprehensive education and mentoring plan. My education plan will provide intensive instruction in the areas of genetics, cancer biology, and epidemiologic methodologies. I have chosen 2 mentors and 3 co-mentors who will supervise a specific portion of my training. Dr. Margaret Spitz (mentor) will provide guidance in cancer epidemiology and in cancer prevention and control methodologies; Dr. Donghui Li (mentor) will offer mentorship in molecular genetics and laboratory methods; Dr. Wenyaw Chan (co-mentor) will supervise the development and application of statistical methods; Dr. Steven Curley (co-mentor) will provide guidance in the clinical features of hepatocellular carcinoma (HCC); and Dr. Hashem El-Serag (co-mentor), an expert in HCV-induced chronic liver diseases will supervise the epidemiological and clinical components of hepatitis C virus (HCV) and liver cirrhosis. I propose two developmental projects that will further my career progress. Both projects will capitalize on the availability of epidemiologic and biologic samples from ongoing funded case-control studies at The University of Texas M. D. Anderson Cancer Center in collaboration with the Baylor College of Medicine (R03 ES11481-01) and the Texas Tobacco Settlement Grant. The main objective is to examine whether genetic variability in factors influencing oxidative stress, inflammatory response, and fibrogenesis may account for some of the variability in disease progression and carcinogenesis in patients with HCV infection, alcohol consumption and diabetes mellitus. In the first project, I propose a case-control study of 300 patients with HCC and 300 healthy controls. The specific aims will be: 1) to compare the frequency of polymorphisms of genes involved in the inflammation and fibrogenesis pathways (i.e., TGF-beta1, TNF-alpha, IL-lbeta, IL-10, IL-11, COX2) between cases and controls; and 2) to integrate the molecular and epidemiological data with the clinical features (i.e., patients' survival, stage of HCC, and tumor differentiation). In the second project, I propose to study 150 patients with HCV and early liver fibrosis (group 1) and 150 patients with HCV and advanced fibrosis (liver cirrhosis; group 2). The specific aims will be: 1) to compare the frequency of polymorphisms of genes involved in antioxidant defense, anti-inflammatory, and fibrogenesis mechanisms (i.e., catalase, glutathione peroxidase, superoxide dismutases, TNF- alpha, and TGF beta1, IL-11, COX2) and genes of DNA repair (i.e., hOGG1 and XRCC1) between group 1 and group. 2). To compare the progression rate of fibrosis (fibrosis stage units/year of HCV infection) by various genotypes of the study genes. Because liver cirrhosis is undoubtedly a precursor lesion for HCC, it would be expected that any genetic factors identified as risk factors for cirrhosis would also increase the risk of HCC. The long-term plan is to refine our risk assessment in patients with liver cirrhosis and HCC so that we can identify high-risk subgroups of candidates for primary and secondary prevention measures.